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Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene. CENPA is a histone H3 variant which is the critical factor determining the kinetochore position(s) on each chromosome in most eukaryotes including humans. CENPA is a protein which epigenetically defines the position of the centromere on each chromosome, determining the position of kinetochore assembly and the final site of sister chromatid cohesion during mitosis. This proteins is frequently accompanied by "centrochromatin"-associated changes to canonical histones and is constitutively present in centromeres. The CENPA protein is a histone H3 variant which replaces one or both canonical H3 histones in a subset of nucleosomes within centromeric chromatin. CENPA has the greatest sequence divergence of the histone H3 variants, with just 48% similarity to canonical histone H3, and has a highly diverged N-terminal tail that lacks many well characterised histone modification sites including H3K4, H3K9 and H3K27. Unusually for a histone, CENPA nucleosomes are not loaded together with DNA replication and are loaded at different cell cycle stages in different organisms: G1 phase in human, M phase in drosophila, G2 in S. pombe. To orchestrate this specialised loading there are CENPA-specific histone chaperones: HJURP in human, CAL1 in drosophila and Scm3 in S. pombe. In most eukaryotes CENPA is loaded into large domains of highly repetitive satellite DNA. The position of CENPA within satellite DNA are heritable at the protein level through a purely epigenetic mechanism. This means that the position of CENPA protein binding to the genome is copied upon cell division to the two daughter cells independent of the underlying DNA sequence. Under circumstances in which CENPA is lost from a chromosome a fail-safe mechanism has been described in human cells in which CENPB recruits CENPA via a satellite DNA binding domain to repopulate the centromere with CENPA nucleosomes. CENPA interacts directly with the inner kinetochore through proteins including CENPC and CENPN.

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Related publications (1)

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin

Pierre Gönczy, Coralie Busso, Benita Wolf, Fernando Romero Balestra, Tessa Vivianne Averink, Alizée Buff

TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule-organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity.

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